Based on growing evidence that histamine functions as a neurotransmitter in brain and recent findings that many psychotropic drugs are potent inhibitors of the histamine-sensitive adenylate cyclase, it is becoming apparent that more attention should be focused on the function of histamine in brain and in mental health. Regulation of histamine synthesis, with emphasis on regulation of histidine decarboxylase, will be examined. This investigation will have a general applicability to the study of neurotransmitter synthesis in the central nervous system. Histidine decarboxylase will be purified, characterized and regulation by protein phosphorylation mediated by cyclic nucleotide-dependent protein kinases as well as the newly-discovered Ca2 ion-dependent protein kinase will be tested. Regulation of histamine synthesis will also be studied in slices and synaptosomes of rat hippocampus to determine the molecular basis for the change in histamine synthesis elicited by K ion-induced depolarization. Experiments on the effects of Ca2 ion and of membrane-permeable derivatives of cyclic nucleotides are also planned. The relationship between H1-receptors and elevation of cAMP and cGMP will be examined in brain slices. Pharmacological analysis will be performed by examining a variety of selective H1-and H2-receptor agonists and antagonists. The effects of a large number of psychotropic drugs on the ability of histamine to elevate cAMP and cGMP levels in slices of guinea pig hippocampus and cortex will be studied.